ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000003.11) (NC_000003.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
27889061 George A et al. (2016) investigated two families in which both parents (and some offspring) were affected with autosomal dominant Waardenburg syndrome type 2A (WS2A) and offspring inheriting MITF variants from both parents were affected with autosomal recessive COMMAD syndrome. In one family, a canonical splice site variant (predicted to cause an out-of-frame loss of an acceptor site at exon 8 of 10) was identified in a mother affected with WS2A. This individual had a daughter diagnosed with COMMAD syndrome, who was compound heterozygous for the maternal variant as well as a missense variant inherited from her father, who was also affected with WS2A.
31427586 Ideura M et al. (2019) used next generation sequencing of a multiple syndromic targeted resequencing gene panel to identify causative variants in 140 patients with hearing loss, including 23 with hearing loss in addition to one or more clinical features associated with Waardenburg syndrome (WS). Among the latter patients, 4 families diagnosed with Waardenburg syndrome 2A were found to carry loss-of-function MITF variants. Specifically, 2 nonsense and 2 frameshift variants were identified that segregated with disease within these families and are predicted to trigger nonsense-mediated decay of variant-carrying transcripts.
30936914 Li W et al. (2019) sequenced Waardenburg syndrome (WS)-associated genes in 90 patients diagnosed with WS. Among these patients, 8 were found to carry loss-of-function MITF variants, consisting of 2 frameshift variants, 5 nonsense variant, and 1 canonical splice site variant. While 4 of these variants are located in the last exon, the remaining 4 variants are located within a region that would be expected to result in nonsense-mediated decay of the relevant transcripts.
20127975 Pingault V et al. (2010) reviewed previously reported MITF variants found in patients with Waardenburg syndrome (WS) or Tietz syndrome. Of the 24 MITF variants described in this paper, 12 are loss-of-function variants (5 frameshift, 2 nonsense, and 5 canonical splice site) identified in patients with WS. All but one of these 12 variants is predicted to trigger nonsense-mediated decay of relevant transcripts.

Haploinsufficiency phenotype comments:

Pathogenic MITF variants are associated with autosomal dominant Waardenburg syndrome type 2A (OMIM # 193510) and autosomal dominant Tietz syndrome (OMIM # 103500), which are two highly phenotypically overlapping disorders (PMID: 27604145, 33506017). Both these disorders are associated with sensorineural hearing loss and pigmentary changes, but these features may be more variable in Waardenburg syndrome type 2A and more severe/penetrant in Tietz syndrome. Autosomal recessive COMMAD (OMIM # 617306) is associated with biallelic pathogenic variants in MITF and also appears to fall within the same phenotypic spectrum as the aforementioned disorders (PMID: 27889061). Notably, only two families have been reported to date with this syndrome. The features in probands with COMMAD associated with compound heterozygous MITF variants include hearing loss, albinism, coloboma, osteopetrosis, microphthalmia, and macrocephaly, while parents and siblings of these probands that were heterozygous for a single pathogenic MITF variant were diagnosed with Waardenburg syndrome type 2.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity